The neuropathogenesis of HIV-associated dementia (HAD) involves a complex interaction between viral proteins, glial cells (microglia and astrocytes), and mediators (cytokines/chemokines and neurotoxins). A growing body of epidemiological, histopathological, and molecular evidence indicates that substances of abuse, such as, opiates and cocaine, foster development of this devastating brain disorder. However, in contrast to opiates, which have high affinity for mu-opioid receptors, kappa-opioid receptor (KOR) ligands have been shown to have neuroprotective effects. The primary hypothesis underlying the research proposed in this grant application is that KOR ligands have a beneficial influence on HIV-1-related brain disease due to their inhibitory effects on neuropathogenic mechanisms of microglia and astrocytes. Based upon a substantial literature indicating that KOR ligands block responses to cocaine, a secondary hypothesis of this research project is that cocaine has a deleterious influence on HIV-1-related brain disease due to its potentiating effects on neuropathogenic mechanisms of microglia and astrocytes and that KOR ligands will block these effects of cocaine. To test these hypotheses, experiments have been designed using several human cell culture models (and functional assays) that are relevant to HIV-1 neuropathogenesis: microglial cells (expression of HIV-1 and neuropathogenic mediators), astrocytes (chemokine production and glutamate uptake), mixed neuronal/glial cells (apoptosis) and neural progenitor cells (proliferation, differentiation, and migration). In the experiments planned, the effects of selected KOR ligands, some of which have shown promise for treatment of cocaine addiction, will be compared to cocaine, and the inhibitory effects of KOR ligands on cocaine will be assessed. Major emphasis will be placed on defining the mechanisms underlying the effects of KOR ligands and cocaine and mechanisms whereby KOR ligands block the neuropathogenic effects of cocaine. Based upon the results of preliminary studies, the research proposed will yield new insights into these mechanisms and as a result this research project will foster the long-term goal of discovering new interventions for the prevention and treatment of HAD.